ORIGINAL RESEARCH ARTICLE Genome-wide scan in Portuguese Island families identifies 5q31–5q35 as a susceptibility locus for schizophrenia and psychosis P Sklar 1,2 , MT Pato 3,4 , A Kirby 2 , TL Petryshen 1,2 , H Medeiros 4 , C Carvalho 4 , A Macedo 5 , A Dourado 5 , I Coelho 5 , J Valente 5 , MJ Soares 5 , CP Ferreira 6 , M Lei 7 , A Verner 7 , TJ Hudson 7 , CP Morley 4 , JL Kennedy 8 , MH Azevedo 4 , E Lander 2 , MJ Daly 2 and CN Pato 3,4 1 Department of Psychiatry, Harvard Medical School, and Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Charlestown, MA, USA; 2 Broad Institute, Cambridge, MA, USA; 3 Veterans Administration, Syracuse, NY, USA; 4 Center for Psychiatric and Molecular Genetics, SUNY/Upstate Medical University, Syracuse, NY, USA; 5 Psicologia Medica, Universidade de Coimbra, Coimbra, Portugal; 6 Psychiatry Service, Ponta Delgada, Azores, Portugal; 7 McGill University and Genome Quebec Innovation Centre, Montreal, Canada H3A 1A4; 8 Clarke Division, Centre for Addiction and Mental Health Toronto, CA, USA Keywords: schizophrenia; bipolar disorder; linkage; genetic Schizophrenia is a common psychiatric disorder with a complex genetic etiology. To understand the genetic basis of this syndrome in Portuguese Island popula- tions, we performed a genome-wide scan of 29 families with schizophrenia, which identified a single region on 5q31–5q35 with strong linkage (NPL ¼ 3.09, P ¼ 0.0012 at D5S820). Empirical simulations set a genome-wide threshold of NPL ¼ 3.10 for significant linkage. Addi- tional support for this locus in schizophrenia comes from higher-density mapping and mapping of 11 addi- tional families. The combined set of 40 families had a peak NPL ¼ 3.28 (P ¼ 0.00066) at markers D5S2112– D5S820. These data and previous linkage findings from other investigators provide strong and consistent evidence for this genomic region as a susceptibility locus for schizophrenia. Exploratory analyses of a novel phenotype, psychosis, in families with schizophrenia and bipolar disorder detected evidence for linkage to the same markers as found in schizophrenia (peak NPL ¼ 3.03, P ¼ 0.0012 at D5S820), suggesting that this locus may be responsible for the psychotic symptoms observed in both diseases. Molecular Psychiatry (2004) 9, 213–218. doi:10.1038/ sj.mp.4001418 Published online 30 December 2003 Schizophrenia is a complex genetic disorder that is found worldwide. Many studies have demonstrated a strong familial genetic component with an approxi- mately 10-fold increased risk for illness in first-degree relatives. 1 This is supported by twin studies that detected a concordance rate of 41–65% for schizophre- nia in monozygotic twin pairs. 2 It is likely that multiple susceptibility loci contribute to this syndrome, and the potential role of gene–gene interactions in pathogenesis must also be considered. Furthermore, the contribution of individual environmental factors to schizophrenia cannot yet be quantified, although their individual effects do not appear to play a role comparable to the genetic background. 2 Despite these difficulties, some consistent linkage signals have emerged, suggesting that true susceptibility loci for schizophrenia have been identified (for a review, see Sklar 3 , Bassett et al 4 and Moises et al 5 ). Recently, specific genes, although not specific polymorphisms, have been identified for several of the linkage regions. 6–10 Geographically and genetically isolated popula- tions have played a key role in disease gene identification. 11 We are studying island populations of Portuguese descent to identify the genetic basis of schizophrenia. The Azorean islands are a nine-island archipelago located in the mid-Atlantic and the island of Madeira is 300 km off the coast of western Africa. Madeira and the Azorean islands had no native population and were settled in the early 1400s almost exclusively by the Portuguese. The settlement of the Azores was a methodical program over a number of years, although the total number of founder families is not known (Costa, 1991). The current population of Azores is 249 000, and of Madeira is 300 000. While the full genetic distinctiveness of this population is not yet known and there are no reports of an excess of recessive Mendelian disorders, the population struc- ture was instrumental in the successful mapping of the gene for Machado-Joseph Disease. 12 Church records on the islands are excellent and provide a mechanism for tracing families for many generations. The islands are served by a modern centralized health system. Our close collaboration with all of the clinicians on the islands allows us unprecedented access to patients and their families. A combination of these factors contributes to the importance of this population to our study. For example, in the course of this study, we have been able to collect a population- based sample with nearly complete ascertainment of schizophrenia cases on the largest Azorean island of Sa ˜o Miguel (population ¼ 150 000). Molecular Psychiatry (2004) 9, 213–218 & 2004 Nature Publishing Group All rights reserved 1359-4184/04 $25.00 www.nature.com/mp